Parkinson's disease affects over 1 million Americans, 15% of whom are under the age of 50. The hallmarks are motor difficulties, but it also impairs cognitive function, particularly in ordering, monitoring and switching among tasks (executive function). Impaired cognitive ability in this domain contributes markedly to occupational problems and impaired quality of life. The goal of the this project is to determine the brain regions involved in these tasks, how function in these regions is altered in Parkinson's disease, and whether a deficiency in the neurotransmitter acetylcholine contributes to deficits in executive function for patients with Parkinson's disease. The proposed experiments use two complementary imaging techniques: functional MRI to determine how the neural system that subserves executive function is disrupted in Parkinson's disease, and perfusion MRI to examine cerebral blood flow changes that correlate with cognitive deficits. We will test the hypothesis that deficits in executive function in PD are related to impairments in the medial frontal areas, since there is greater cell loss in these areas. The lateral frontal cortex is often assumed to be the cause. The second hypothesis is that these specific behavioral and regional deficits are caused, in part, by a deficiency in the neurotransmitter acetylcholine. PD patients who have executive dysfunction and demographically-matched controls will receive either the cholinesterase inhibitor donepezil or placebo in a double-blind, crossover design. They will then undergo behavioral testing, fMRI with phonemic fluency, and perfusion MRI. The fMRI data will determine the neural regions involved in a specific executive function task, phonemic fluency, and test how these regions are affected in PD. The perfusion MRI results will address what changes in cerebral blood flow are associated with this executive impairment. By contrasting the two imaging paradigms after donepezil with those after placebo, we will test the role of a cholinergic deficiency in the executive dysfunction seen in PD. Taken together; the proposed studies will provide insight in the regional and neurochemical basis of cognitive impairments in Parkinson's disease. It will also test whether cholinergic repletion is a potential mechanism for treating these deficits in executive function using a series of behavioral tests, functional brain imaging, and measures of cerebral blood flow with perfusion MRI. Project Narrative The primary goal of this proposal is to determine the regional and neurochemical basis of executive dysfunction in Parkinson's disease. We plan on using specifically designed cognitive measures as well as two complementary brain imaging techniques, functional MRI and perfusion MRI, to determine the regional basis of the deficit. We then propose a cholinergic probe, applied in a double-blind, placebo-controlled manner, to determine the role that a deficiency in acetylcholine may play in both the behavioral deficits and the dysfunction in the neural systems. [unreadable] [unreadable] [unreadable]